Acid-sensitive groups

Selective oxidation of secondary alcohols to ketones is usually performed with CrOj/HjSO, I I in acetone (Jones reagent) or with CrOjPyj (Collin s reagent) in the presence of acid-sensitive groups (H.G. Bosche, 1975 C. Djerassi, 1956 W.S. Allen, 1954). As mentioned above, a,)S-unsaturated secondary alcohols are selectively oxidized by MnOj (D.G. Lee, 1969 D. Arndt, 1975) or by DDQ (D. Walker, 1967 H.H. Stechl, 1975). 

Instead of sodium nitrite, isoamyl nitrite is sometimes used as a nitrosating agent in synthesis of the benzotriazole ring. With this reagent, the reaction conditions are very mild allowing survival of acid sensitive groups. In an example of such a reaction, methyl 3,4-diamino-2-methoxybenzoate 1286 is treated with isoamyl nitrite at room temperature. The reaction is fast and provides methyl 4-methoxybenzotriazole-5-carboxylate 1287 in 62% yield, isolated by simple filtration off the precipitate (Equation 31) <2006JME4762>. 

K Barlos, O Chatzi, D Gatos, G Stavropoulos, T Tsegenidis. Fmoc-His(Mmt)-OH and Fmoc-His(Mtt)-OH. Two new histidine derivatives N""-protected with highly acid-sensitive groups. Preparation, properties and use in peptide synthesis, (dimeth-ylsilyldichloride) Tetrahedron Lett 32, 475, 1991. 

Under anhydrous conditions, side reactions due to hydroxyl or perhydroxyl radical species can be avoided. Tetrahydropyran and tetrahydrofuran ethers were prepared in good to excellent yields (85-97%) from the corresponding primary and secondary alcohols and THP and THE as a solvent using (w-Bu4N)2S208. Under these reaction conditions the sulfide group and acid-sensitive groups such as aUylic hydroxyl or an acetal moiety remain intact (equation 27). 

K2CO3 is more effective, MgSO should not be used if acid-sensitive groups (c.g. C C-O. C-O-CH-O) arc present in the carbinol. 

Chlorohydrins.1 Epoxides are converted into chlorohydrins by TiCl4 and DBU in CH2C12 at 25°. The conditions allow survival of acid-sensitive groups such as acetals. Yields are lower when DBU is replaced by DMAP. 

The examples discussed above constitute a selection of recent applications of the acid and basic hydrolysis of (3-lactams in synthesis. Hydrolysis and alcoholysis of (3-lactams can also be effected under roughly neutral reaction conditions when enzymes are the promoters [47]. The (3-lactamases catalyzed hydrolysis of (3-lactams is an efficient process for a broad spectrum of substrates, including those (3-lactams with base or acid sensitive groups [12-14]. This process proceeds through an acyl enzyme intermediate to give ring opened (3-amino acids. The class C (3-lactamases in particular, in Scheme 9, have the ability to catalyze the alcoholysis reaction and hence (3-amino esters are the products formed. 

Note. (1) These reaction conditions are used for the oxidation of decan-l-ol, hexane-1, 6-diol and oct-2-yn-l-ol. In the case of alcohols where acid-sensitive groups are also present (e.g. tetrahydropyranyl ethers), sodium acetate is added to buffer the reaction mixture alternatively pyridinium dichromate may be used.99... 

The preparation of phenols by the hydrolysis of diazonium salts with hot aqueous acid, and by a recent milder procedure suitable for diazonium salts having additional acid-sensitive groups, is discussed in Section 6.7.1, p. 922, and illustrated in Expt 6.69. Although these methods enable an aromatic hydrocarbon system to be converted in good yield into a phenol via the corresponding nitro and amino derivatives, the shorter route involving the alkaline fusion of the sulphonic acid discussed above may often be preferred. 

Aldehydes can be allylated with allyltributylstannane using cerium(III) chloride in acetonitrile, a method particularly suitable for substrates bearing acid-sensitive groups.185... 

The resultant sulfate ester can be converted to the alcohol by acid hydrolysis. If an acid-sensitive group is present, this hydrolysis is still successful through use of a catalytic amount of sulfuric acid in the presence of 0.5-1.0 equivalents of water with tetrahydrofuran as solvent. The use of base in the formation of the cyclic sulfates themselves can also alleviate problems associated with acid-sensitive groups.174175... 

Basic conditions used when there are acid sensitive groups in the molecule. 

KMnO and NaOH can be used in place of Na2Cr20a and l-l2 SO if there are acid sensitive groups present in the molecule. 

Cyclic sulfates can even be prepared from diols containing acid-sensitive groups acetonide, silyloxy) by reaction with thionyl chloride and N(C2H5)3 followed by oxidation of the isolated sulfites with Ru04 (catalytic). After reactions with a nucleophile, the resulting sulfate esters can be hydrolyzed by water (0.5-1.0 equiv.) in THF catalyzed by H2S04. The use of a minimal amount of water is crucial for chemoselectivity.2... 

S-Acetals and Op5-acetals may be deprotected with periodic acid.lfiff The mildness of the reagent is illustrated by the oxidative hydrolysis of dithioacetal 79.1 to ketone 793 without migration of the Z double bond or attack on the dienyl ester moiety [Scheme 2,79]. Other acid sensitive groups like /erf-butyldimethylsi-lyl ethers and acetals are unaffected by the reaction conditions. 

O-tert-Butyl trichloroacetimidate, prepared in 70% yield by reacting potassium rerr-butoxide with trichloroacetonitrile, reacts with carboxylic acids and alcohols in the presence of a catalytic amount of boron trifluoride etherate at room temperature in cyclohexane-dichloromethane [Scheme 6.35], 7 The method also converts alcohols to ferr-butyl ethers (see section 4.3.2). A very similar reaction that allows /erf-butylation under essentially neutral conditions on a large scale involves reaction of a carboxylic acid with 3-4 equivalents of JV,N -di-isopropyl-Orerf-butylisourea88 [Scheme 6,36].56S9 The reaction proceeds via a tertiary carbocation ion intermediate and since capture of the cation is inefficient, excess isourea is required. The presence of alcohols is tolerated but not thiols or unhindered amines. The reaction conditions are compatible with a range of acid sensitive groups such as AMrityl derivatives and cydopentylidene acetals.90... 

Oxidation of alcohols. The reactivity of PDC is increased by acetic anhydride. Primary and secondary alcohols are oxidized efficiently with 0.6-0.7 equiv of PDC and 3 equiv. of Ac.O in CfLCl, at 40°. Addition of DMF in the oxidation of primary alcohols retards further oxidation to the carboxylic acid. Acid-sensitive groups are stable to the conditions. 

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